Trial Review

Reset your password and enable multi-factor authentication (MFA)


For ANZCTR account holders: to help ensure the cyber safety of your account, you’ll need to reset your password and set-up multi-factor authentication (MFA) as per the instructions below.


  1. Go to the Login page, click ‘reset password’ and follow the instructions.
  2. Check your email for the link to set a new password.
  3. Create a new password that meets requirements.
  4. Return to the Login page and enter your new password. A verification code will be sent to your email.
  5. Check your email for the code and enter it on the Login page. If the code is entered incorrectly, you can re-enter the correct one or request a new one.

Learn more about MFA and its importance on the Australian Signals Directorate website.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT01345630




Registration number
NCT01345630
Ethics application status
Date submitted
27/04/2011
Date registered
2/05/2011
Date last updated
14/01/2016

Titles & IDs
Public title
Comparative Trial Of Maraviroc Versus Emtricitabine/Tenofovir Both With Darunavir/Ritonavir In Antiretroviral-Naive Patients Infected With CCR5 Tropic HIV 1
Scientific title
A Multicenter, Randomized, Double-Blind, Comparative Trial Of Maraviroc + Darunavir/Ritonavir Versus Emtricitabine/Tenofovir + Darunavir/Ritonavir For The Treatment Of Antiretroviral-Naive Hiv-Infected Patients With Ccr5-Tropic Hiv-1
Secondary ID [1] 0 0
2010-021785-30
Secondary ID [2] 0 0
A4001095
Universal Trial Number (UTN)
Trial acronym
MODERN
Linked study record

Health condition
Health condition(s) or problem(s) studied:
HIV-1 0 0
Condition category
Condition code

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Maraviroc
Treatment: Drugs - Emtricitabine/tenofovir
Treatment: Drugs - darunavir/ritonavir 800/100 mg
Treatment: Drugs - placebo for emtricitabine/tenofovir
Treatment: Drugs - placebo for maraviroc

Experimental: Maraviroc - Maraviroc 150 mg once daily plus darunavir/ritonavir 800/100 mg once daily plus placebo for emtricitabine/tenofovir once daily.

Active comparator: Emtricitabine/tenofovir - Emtricitabine/tenofovir 200/300 mg once daily plus darunavir/ritonavir 800/100 mg once daily plus placebo for maraviroc once daily.


Treatment: Drugs: Maraviroc
Maraviroc tablet 150 mg once daily for 96 weeks.

Treatment: Drugs: Emtricitabine/tenofovir
Emtricitabine/tenofovir tablet 200/300 mg once daily for 96 weeks.

Treatment: Drugs: darunavir/ritonavir 800/100 mg
darunavir/ritonavir 800/100 mg

Treatment: Drugs: placebo for emtricitabine/tenofovir
placebo for emtricitabine/tenofovir

Treatment: Drugs: placebo for maraviroc
placebo for maraviroc
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Percentage of Participants With Plasma HIV-1 RNA <50 Copies/mL.
Assessment method [1] 0 0
The proportion of participants who achieved HIV-1 RNA \<50 copies/mL at week 48 was assessed according to Food and Drug Administration's (FDA's) Missing, Switch, Discontinuation'=Failure (MSDF) Snapshot algorithm. The algorithm used the plasma HIV-1 RNA in the Week 48 visit window, followed the "virology-first principle" and considers a participant who has a missing plasma HIV-1 RNA, or switches to prohibited ARV regimen or discontinues from the study or study drug for any reason, or dies, as a failure.
Timepoint [1] 0 0
Week 48
Secondary outcome [1] 0 0
Frequency of Adverse Events (AE).
Assessment method [1] 0 0
Number of participants with treatment-emergent non serious AEs
Timepoint [1] 0 0
Week 96
Secondary outcome [2] 0 0
Number of Participants With Grade 3 or 4 AEs
Assessment method [2] 0 0
Number of participants with grade 3 or 4 AEs are presented here.
Timepoint [2] 0 0
Week 96
Secondary outcome [3] 0 0
Number of Participants Who Discontinued Due to AEs
Assessment method [3] 0 0
Number of participants who discontinued due to AEs are reported here. Three participants (two from the MVC+DRV/r arm and one from the FTC/TDF+DRV/r arm) were not considered as discontinued due to AE because other reasons for discontinuation were prioritized for these participants.
Timepoint [3] 0 0
Week 96
Secondary outcome [4] 0 0
Number of Treatment-related AEs
Assessment method [4] 0 0
Number of treatment-related AEs are presented here.
Timepoint [4] 0 0
Week 96
Secondary outcome [5] 0 0
Number of Participants With Treatment-emergent Serious Adverse Events
Assessment method [5] 0 0
Total number of participants with treatment-emergent serious adverse events are reported
Timepoint [5] 0 0
Week 96
Secondary outcome [6] 0 0
Number of Participants With Abnormal Laboratory Values
Assessment method [6] 0 0
Number of participants with laboratory abnormalities are reported
Timepoint [6] 0 0
Week 96
Secondary outcome [7] 0 0
Severity of Abnormal Laboratory Values
Assessment method [7] 0 0
Number of participants who had clinically significant laboratory abnormalities of Grade 3 and Grade 4 according to DAIDS. Abnormality incidence of highest grade was reported for a labcode for each individual participant.
Timepoint [7] 0 0
Week 96
Secondary outcome [8] 0 0
The Relationship Between the Proportion of Participants With Plasma HIV-1 RNA <50 Copies/mL at the Week 48 and the Screening Tropism Test (Genotype Test or ESTA).
Assessment method [8] 0 0
The relationship of the proportion of participants achieving HIV-1 RNA \<50 copies/mL at Week 48 with the screening tropism test for the MVC containing regimen was analyzed. Virologic response for a participant at Week 48 was derived using the FDA's Snapshot MSDF algorithm. Difference in proportions of patients with plasma HIV-1 RNA \<50 copies/mL at week 48 between the maraviroc and the emtricitabine/tenofovir treatment arms, with two-sided 95% confidence interval, among patients who are R5 by genotype (including some who were originally randomized to ESTA and are R5 by genotype upon retesting), were calculated via the Maximum Likelihood method. The estimate was adjusted for the screening plasma HIV RNA level (\<100,000 vs. =100,000) copies/mL via the Mantel Haenszel (MH) method.
Timepoint [8] 0 0
Week 48
Secondary outcome [9] 0 0
Virologic Outcomes at Week 48 Using Protocol-Defined Treatment Failure (PDTF).
Assessment method [9] 0 0
Per the protocol participants who meet the following criteria were regarded as PDTFs requiring a confirmatory plasma HIV-1 RNA determination: • Decrease in plasma HIV-1 RNA \<1 log10 from baseline after Week 4 unless plasma HIV-1 RNA is \<50 copies/mL, or • Plasma HIV-1 RNA \>1.0 log10 above the nadir value after Week 4 where the nadir is the lowest plasma HIV-1 RNA concentration, or • Plasma HIV-1 RNA =50 copies/mL at any time after Week 24, or • Plasma HIV-1 RNA =50 copies/mL after suppression to \<50 copies/mL on two consecutive visits, or • Decrease in plasma HIV-1 RNA =2 log10 from baseline on or after Week 12 unless plasma HIV-1 RNA is \<400 copies/mL. Decrease in plasma HIV-1 RNA =2 log10 from baseline on or after Week 12 unless plasma HIV-1 RNA is \<50 copies/mL (before August 30 2012) or \<400 copies/mL (after August 30 2012).
Timepoint [9] 0 0
Week 48
Secondary outcome [10] 0 0
Tropism Change Between Screening or Baseline and PDTF
Assessment method [10] 0 0
For participants meeting the PDTF criteria, tropism was assessed using the original randomized and alternate assays (ie, both genotype testing and ESTA). Data reported here corresponds to the timepoint at or after PDTF.
Timepoint [10] 0 0
Week 48
Secondary outcome [11] 0 0
Number of Participants With Viral Resistance to Maraviroc (Maraviroc Treated Participants Only) in Participants Meeting PDTF Criteria.
Assessment method [11] 0 0
For participants meeting the PDTF criteria, viral resistance to maraviroc for maraviroc treated participants was assessed in patients with R5 virus at failure. The resistance level is calculated by reference to a laboratory strain of virus that is analyzed in parallel with the clinical isolate to identify 50% inhibitory concentrations (IC50). The maximal percent inhibition is the percent inhibition that is achieved in a titration of the drug at high concentrations when the addition of more drug does not result in increased inhibition. Maximal percent inhibition is obtained in the same way as the titration for IC50, but the key measure is of the plateau height of percent inhibition, where increased concentration of maraviroc does not result in additional inhibition. This is consistent with the virus developing some ability to use maraviroc-bound CCR5 for entry. A significant change in IC50 is not required for this mechanism.
Timepoint [11] 0 0
Week 48
Secondary outcome [12] 0 0
Number of Participants With Resistance to Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTI), Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI), and Protease Inhibitors (PI) in Participants Meeting PDTF Criteria
Assessment method [12] 0 0
For participants meeting the PDTF criteria, viral resistance (both genotypic and phenotypic) to NRTI, NNRTI, and PI's were assessed at Baseline and on-treatment. The assessment was performed using the overall (i.e. net) susceptibility score provided using the PhenoSense GT assay. The number of participants with successful assessments were 15/17 for the MVC+DRV/r arm and 3/3 for the FTC/TDF+DRV/r arm.
Timepoint [12] 0 0
Week 48
Secondary outcome [13] 0 0
Absolute Change From Baseline in Immune Cell Function at Week 48: Lymphocyte Marker Cluster of Differentiation 4 (CD4, Cell/mm^3)
Assessment method [13] 0 0
The differences in the magnitude of changes in CD4+ at Baseline and at Week 48 for maraviroc versus emtricitabine/tenofovir were compared.
Timepoint [13] 0 0
Baseline, Week 48
Secondary outcome [14] 0 0
Percent Change From Baseline in Immune Cell Function at Week 48: Lymphocyte Activation Marker CD4 (%)
Assessment method [14] 0 0
The differences in the magnitude of changes in CD4+ from Baseline through Week 48 for maraviroc versus emtricitabine/tenofovir were compared.
Timepoint [14] 0 0
Baseline, Week 48
Secondary outcome [15] 0 0
Absolute Change From Baseline in Immune Cell Function at Week 48: Lymphocyte Marker Cluster of Differentiation 8 (CD8, Cell/mm^3)
Assessment method [15] 0 0
The differences in the magnitude of changes in CD8+ cell counts from baseline through Week 48 for maraviroc versus emtricitabine/tenofovir were compared.
Timepoint [15] 0 0
Baseline, Week 48
Secondary outcome [16] 0 0
Percent Change From Baseline in Immune Cell Function at Week 48: Lymphocyte Activation Marker CD8 (%)
Assessment method [16] 0 0
The differences in the magnitude of changes in CD8+ cell counts from Baseline through Week 48 for maraviroc versus emtricitabine/tenofovir were compared.
Timepoint [16] 0 0
Baseline, Week 48
Secondary outcome [17] 0 0
Absolute Change in CD4+/CD8+ Ratio From Baseline to Week 48
Assessment method [17] 0 0
The differences in the magnitude of changes in CD4+/CD8+ ratio from Baseline through Weeks 48 for maraviroc versus emtricitabine/tenofovir were compared.
Timepoint [17] 0 0
Baseline, Week 48
Secondary outcome [18] 0 0
Changes in Peripheral Fat Distribution Using Dual Energy X-ray Absorptiometry [DEXA] Scan From Baseline and at Week 48.
Assessment method [18] 0 0
A sub-study was conducted in which the participants underwent whole-body DEXA scans to evaluate peripheral fat tissue estimates for left and right arms and legs and truncal fat mass and truncal lean mass. Truncal abdominal fat were estimated from the DEXA scan field set on the torso. The effects on estimates of fat mass and lean mass were addressed by providing LSMs of change from baseline.
Timepoint [18] 0 0
Week 48
Secondary outcome [19] 0 0
Changes in Trunk to Limb Fat Distribution Using DEXA Scan From Baseline and at Week 48
Assessment method [19] 0 0
A sub-study was conducted in which the participants underwent whole-body DEXA scans to evaluate peripheral fat tissue estimates for left and right arms and legs and truncal fat mass and truncal lean mass. Truncal abdominal fat were estimated from the DEXA scan field set on the torso. The effects on estimates of fat mass and lean mass were addressed by providing LSMs of change from baseline.
Timepoint [19] 0 0
Week 48
Secondary outcome [20] 0 0
Changes in Bone Mineral Density (Using DEXA Scan and Serum Markers) From Baseline and at Week 48 - Total Hip BMD
Assessment method [20] 0 0
Bone mineral density was evaluated by DEXA scan in a subset of participants who consented to these evaluations. The effects on BMD were addressed by providing LSMs of change from baseline bone mineral density of the lumbar spine (L1-L4), left total hip and femoral neck as measured by the DEXA scan.
Timepoint [20] 0 0
Week 48
Secondary outcome [21] 0 0
Changes in Bone Mineral Density (Using DEXA Scan and Serum Markers) From Baseline and at Week 48 - Femoral Neck BMD
Assessment method [21] 0 0
Bone mineral density was evaluated by DEXA scan in a subset of participants who consented to these evaluations. The effects on BMD were addressed by providing LSMs of change from Baseline bone mineral density femoral neck as measured by the DEXA scan.
Timepoint [21] 0 0
Week 48
Secondary outcome [22] 0 0
Changes in Bone Mineral Density (Using DEXA Scan and Serum Markers) From Baseline and at Week 48 - AP Lumbar Spine (L1 - L4) BMD
Assessment method [22] 0 0
Bone mineral density was evaluated by DEXA scan in a subset of participants who consented to these evaluations. The effects on BMD were addressed by providing LSMs of change from baseline bone mineral density of the lumbar spine (L1-L4) as measured by the DEXA scan.
Timepoint [22] 0 0
Week 48
Secondary outcome [23] 0 0
Change in Bone Turnover Markers From Baseline and at Week 48 - Blood Osteocalcin
Assessment method [23] 0 0
Bone turnover marker, osteocalcin, was collected in the subset of participants participating in the DEXA scan sub-study.
Timepoint [23] 0 0
Week 48
Secondary outcome [24] 0 0
Change in Bone Turnover Markers From Baseline and at Week 48 - Type 1 Collagen Peptide (CTX-1)
Assessment method [24] 0 0
Bone turnover marker, C-telopeptide of type 1 collagen (CTx), was collected in the subset of participants participating in the DEXA scan sub-study.
Timepoint [24] 0 0
Week 48

Eligibility
Key inclusion criteria
* Plasma HIV-1 RNA equal to or greater than 1,000 copies/mL measured at the Screening Visit.
* CD4 count equal to or greater than 100 cells/mm3 at Screening.
* Have only R5 HIV 1 at Screening as verified by a randomized tropism assay.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
* Prior treatment with any other HIV antiretroviral therapy for more than 14 days at any time.
* Any evidence of genotypic/phenotypic resistance to darunavir, tenofovir, and emtricitabine.
* CXCR4 using virus detected using randomized tropism determination or repeated failure to obtain an interpretable tropism result.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Stopped early
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
1/09/2011
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
1/01/2014
Sample size
Target
Accrual to date
Final
813
Recruitment in Australia
Recruitment state(s)
NSW,QLD,VIC
Recruitment hospital [1] 0 0
East Sydney Doctors - Darlinghurst
Recruitment hospital [2] 0 0
Holdsworth House General Practice - Darlinghurst
Recruitment hospital [3] 0 0
St Vincent's Hospital - Darlinghurst
Recruitment hospital [4] 0 0
Taylor Square Private Clinic - Surry Hills
Recruitment hospital [5] 0 0
Brisbane Sexual Health and HIV Service - Brisbane
Recruitment hospital [6] 0 0
Melbourne Sexual Health Centre - Carlton
Recruitment hospital [7] 0 0
Clinical Research Unit, Infectious Diseases - Melbourne
Recruitment postcode(s) [1] 0 0
2010 - Darlinghurst
Recruitment postcode(s) [2] 0 0
2010 - Surry Hills
Recruitment postcode(s) [3] 0 0
4000 - Brisbane
Recruitment postcode(s) [4] 0 0
3053 - Carlton
Recruitment postcode(s) [5] 0 0
3004 - Melbourne
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Alabama
Country [2] 0 0
United States of America
State/province [2] 0 0
California
Country [3] 0 0
United States of America
State/province [3] 0 0
Colorado
Country [4] 0 0
United States of America
State/province [4] 0 0
Connecticut
Country [5] 0 0
United States of America
State/province [5] 0 0
District of Columbia
Country [6] 0 0
United States of America
State/province [6] 0 0
Florida
Country [7] 0 0
United States of America
State/province [7] 0 0
Georgia
Country [8] 0 0
United States of America
State/province [8] 0 0
Illinois
Country [9] 0 0
United States of America
State/province [9] 0 0
Iowa
Country [10] 0 0
United States of America
State/province [10] 0 0
Louisiana
Country [11] 0 0
United States of America
State/province [11] 0 0
Massachusetts
Country [12] 0 0
United States of America
State/province [12] 0 0
Michigan
Country [13] 0 0
United States of America
State/province [13] 0 0
Minnesota
Country [14] 0 0
United States of America
State/province [14] 0 0
Missouri
Country [15] 0 0
United States of America
State/province [15] 0 0
Nebraska
Country [16] 0 0
United States of America
State/province [16] 0 0
New Jersey
Country [17] 0 0
United States of America
State/province [17] 0 0
New York
Country [18] 0 0
United States of America
State/province [18] 0 0
North Carolina
Country [19] 0 0
United States of America
State/province [19] 0 0
Ohio
Country [20] 0 0
United States of America
State/province [20] 0 0
Texas
Country [21] 0 0
United States of America
State/province [21] 0 0
Washington
Country [22] 0 0
Austria
State/province [22] 0 0
Wien
Country [23] 0 0
Belgium
State/province [23] 0 0
Antwerpen
Country [24] 0 0
Belgium
State/province [24] 0 0
Brussels
Country [25] 0 0
Belgium
State/province [25] 0 0
Bruxelles
Country [26] 0 0
Belgium
State/province [26] 0 0
Gent
Country [27] 0 0
Belgium
State/province [27] 0 0
Liege
Country [28] 0 0
Canada
State/province [28] 0 0
British Columbia
Country [29] 0 0
Canada
State/province [29] 0 0
Ontario
Country [30] 0 0
Canada
State/province [30] 0 0
Quebec
Country [31] 0 0
Denmark
State/province [31] 0 0
Hvidovre
Country [32] 0 0
Denmark
State/province [32] 0 0
Koebenhavn OE
Country [33] 0 0
Denmark
State/province [33] 0 0
Odense
Country [34] 0 0
Finland
State/province [34] 0 0
Helsinki
Country [35] 0 0
France
State/province [35] 0 0
Cedex 02
Country [36] 0 0
France
State/province [36] 0 0
Cedex 12
Country [37] 0 0
France
State/province [37] 0 0
Cedex 18
Country [38] 0 0
France
State/province [38] 0 0
Bordeaux cedex
Country [39] 0 0
France
State/province [39] 0 0
Creteil
Country [40] 0 0
France
State/province [40] 0 0
Le Kremlin Bicetre
Country [41] 0 0
France
State/province [41] 0 0
LYON Cedex 4
Country [42] 0 0
France
State/province [42] 0 0
Montpellier
Country [43] 0 0
France
State/province [43] 0 0
Nantes
Country [44] 0 0
France
State/province [44] 0 0
Paris Cedex 10
Country [45] 0 0
France
State/province [45] 0 0
Paris
Country [46] 0 0
France
State/province [46] 0 0
Strasbourg Cedex
Country [47] 0 0
France
State/province [47] 0 0
Tourcoing
Country [48] 0 0
Germany
State/province [48] 0 0
Berlin
Country [49] 0 0
Germany
State/province [49] 0 0
Bonn
Country [50] 0 0
Germany
State/province [50] 0 0
Frankfurt am Main
Country [51] 0 0
Germany
State/province [51] 0 0
Hamburg
Country [52] 0 0
Germany
State/province [52] 0 0
Koeln
Country [53] 0 0
Germany
State/province [53] 0 0
Muenchen
Country [54] 0 0
Hungary
State/province [54] 0 0
Budapest
Country [55] 0 0
Italy
State/province [55] 0 0
Milano
Country [56] 0 0
Netherlands
State/province [56] 0 0
Utrecht
Country [57] 0 0
Poland
State/province [57] 0 0
Bydgoszcz
Country [58] 0 0
Poland
State/province [58] 0 0
Warszawa
Country [59] 0 0
Poland
State/province [59] 0 0
Wroclaw
Country [60] 0 0
Portugal
State/province [60] 0 0
Amadora
Country [61] 0 0
Portugal
State/province [61] 0 0
Lisboa
Country [62] 0 0
Portugal
State/province [62] 0 0
Porto
Country [63] 0 0
Puerto Rico
State/province [63] 0 0
Bayamon
Country [64] 0 0
Puerto Rico
State/province [64] 0 0
Ponce
Country [65] 0 0
Puerto Rico
State/province [65] 0 0
Rio Piedras
Country [66] 0 0
Puerto Rico
State/province [66] 0 0
San Juan
Country [67] 0 0
Spain
State/province [67] 0 0
Barcelona
Country [68] 0 0
Spain
State/province [68] 0 0
Alicante
Country [69] 0 0
Spain
State/province [69] 0 0
Cordoba
Country [70] 0 0
Spain
State/province [70] 0 0
Madrid
Country [71] 0 0
Spain
State/province [71] 0 0
Sevilla
Country [72] 0 0
Sweden
State/province [72] 0 0
Goteborg
Country [73] 0 0
Sweden
State/province [73] 0 0
Malmo
Country [74] 0 0
Sweden
State/province [74] 0 0
Stockholm
Country [75] 0 0
Switzerland
State/province [75] 0 0
Basel
Country [76] 0 0
Switzerland
State/province [76] 0 0
Bern
Country [77] 0 0
Switzerland
State/province [77] 0 0
St. Gallen
Country [78] 0 0
Switzerland
State/province [78] 0 0
Zurich
Country [79] 0 0
United Kingdom
State/province [79] 0 0
Birmingham
Country [80] 0 0
United Kingdom
State/province [80] 0 0
Brighton
Country [81] 0 0
United Kingdom
State/province [81] 0 0
Edinburgh
Country [82] 0 0
United Kingdom
State/province [82] 0 0
London
Country [83] 0 0
United Kingdom
State/province [83] 0 0
Manchester

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
ViiV Healthcare
Country
Other collaborator category [1] 0 0
Commercial sector/industry
Name [1] 0 0
Pfizer
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Public notes

Contacts
Principal investigator
Name 0 0
Pfizer CT.gov Call Center
Address 0 0
Pfizer
Country 0 0
Phone 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Email 0 0
Contact person for scientific queries

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

No documents have been uploaded by study researchers.

Results are available at https://clinicaltrials.gov/study/NCT01345630